Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the Synthesis of 2-Substituted Piperazines under Batch and Flow Conditions

Article abstract of DOI:10.1021/acs.orglett.0c01759

Piperazines are privileged scaffolds in medicinal chemistry. Disclosed herein is a visible-light-promoted decarboxylative annulation protocol between a glycine-based diamine and various aldehydes to access 2-aryl, 2-heteroaryl, as well as 2-alkyl piperazines. The iridium-based complex [Ir(ppy)2(dtbpy)]PF6 and carbazolyl dicyanobenzene 4CzIPN were found to be the photocatalysts of choice to efficiently perform the transformation under mild conditions, whether in batch or in continuous mode.

Full text of DOI:10.1021/acs.orglett.0c01759

pubs.acs.org/OrgLett
Letter
Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the
Synthesis of 2‑Substituted Piperazines under Batch and Flow
Conditions
Robin Gueret, Lydie Pelinski, Till Bousquet,* Mathieu Sauthier, Vincent Ferey, and Antony Bigot*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01759
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ABSTRACT: Piperazines are privileged scaffolds in medicinal
chemistry. Disclosed herein is a visible-light-promoted decarbox-
ylative annulation protocol between a glycine-based diamine and
various aldehydes to access 2-aryl, 2-heteroaryl, as well as 2-alkyl
piperazines. The iridium-based complex [Ir(ppy)2(dtbpy)]PF6 and
carbazolyl dicyanobenzene 4CzIPN were found to be the
photocatalysts of choice to efficiently perform the transformation
under mild conditions, whether in batch or in continuous mode.
he piperazine skeleton is the third most common
Scheme 1. Synthesis of 2-Substituted Piperazines
T
nitrogen heterocyclic core encountered in approved
pharmaceuticals (Figure 1).1 The construction of this saturated
of a safer, tin-free SLAP protocol making use of diaminosilyl
reagents. In both protocols, these key reagents react with either
aldehydes or ketones to generate the corresponding aldimines/
ketimines, followed by carbon-centered radical generation.
This nucleophilic radical then adds to the aldimine/ketimine
group in a 6-endo-trig mode, to generate the six-membered ring
and the nitrogen-centered aminyl radical, the reduction of
which generates the nitrogen-anion that is finally protonated
by the solvent. (See Scheme 1.) Very recently, on the basis of
the same photoinitiated concept, an alternative strategy was
described from amino-dihydropyridine (DHP) reagents. In-
deed, similarly to alkyl silicon reagents, it was previously found
that the 4-alkyl Hantzsch ester moiety can lead to the
Figure 1. Examples of drugs containing a piperazine core.
six-membered ring scaffold has thus been extensively
investigated.2 However, efficient synthetic pathways to access
α-substituted piperazines are somewhat limited. Available
approaches include the di- or monoketopiperazine reduction,
the Mitsunobu transformation,3 hydroamination,4 condensa-
tion of diamines on diols,5 α-bromo ester or epoxide
derivatives,6 lithiation/trapping of N-Boc piperazines,7 and
photoredox catalysis.8 In 2013, a breakthrough was achieved by
Bode’s group when first developing the SnAP (Tin Amine
Protocol),9 shortly followed by the photocatalytic SLAP
(SiLicon Amine Protocol) variant (Scheme 1).10 These
straightforward strategies allow access to a wide variety of
saturated N-heterocycles including piperazines, morpholines,
thiomorpholines, oxazepines, and diazepines. For the prepara-
tion of piperazines, the SnAP reagents are toxic diaminos-
tannane compounds, hence the development by Bode’s group
Received: May 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01759
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Table 1. Optimization of the Piperazine Synthesis
b
entry
base
aldehyde 2a (equiv)
photocatalyst (mol %)
irradiation time (h)
yield (%)
1
2
3
4
5
6
7
8
KOH
Cs2CO3
K2HPO4
CsF
TMG
DBU
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
1
1
1
1
1
1
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (1)
Ir1 (0.5)
Ir1 (0.1)
Ir2 (1)
Ru(bpy)3Cl2 (1)
4CzIPN (1)
4CzIPN (5)
none
3
3
3
3
3
3
3
0.5
3
3
3
3
3
3
3
3
3
3
3
90
60
25
38
57
60
95
95
90
85
75
90
85
33
33
70
92
0
9
10
11
12
13
14
15
16
17
18
c
19
Ir1 (1)
0
a
Each reaction was performed at room temperature, under blue-light irradiation (34 W) on a 0.1 mmol scale of 1 in 0.05 M concentration in a
b
MeCN/MeOH (4/1) degassed solution in the presence of 4.1 equiv of base. NMR yields using 1,3,5-trimethoxybenzene as an internal standard.
c
Experiment performed in the dark.
corresponding alkyl radical by oxidative single-electron trans-
fer.11
reacted in a one to 1:1 ratio with diamino carboxylic acid 1.
Several inorganic bases (KOH, Cs2CO3, K2HPO4, and CsF) as
well as organic ones (TMG, tetramethylguanidine; DBU, 1,8-
diazabicyclo[5,4,0]undec-7-ene) were evaluated (entries 1−6).
After 3 h of irradiation, we were delighted to observe, in all
cases, the formation of the desired cyclized product piperazine
3a. Although acceptable yields were obtained with both
organic bases and Cs2CO3, the best result was achieved in the
presence of KOH, yielding 90% of 3a (entry 1). Increasing the
proportion of aldehyde 2a to 1.4 equiv led to an increase in
yield to 95% regardless of whether the irradiation time was
maintained at 3 h or, more interestingly, decreased to 30 min
(entries 7 and 8).
Next, the catalytic performance of various photocatalysts,
including iridium- or ruthenium-based complexes and the
purely organic carbazolyl dicyanobenzene 4CzIPN, was
evaluated (entries 11−17). From this survey, Ir1 appears to
be the most active and, interestingly, remains satisfactory with
a catalyst loading as low as 0.1 mol % (entries 11−14). It
should be emphasized that the easily accessible organo-
photocatalyst 4CzIPN showed remarkable effectiveness to
perform the reaction, although 5 mol % loading was required
(entries 16 and 17). Blank experiments were conducted either
In 2014, the group of MacMillan extended the photo-
catalyzed oxidative decarboxylation on amino acids.12 This
triggered significant interest oriented toward the application of
such processes in a wide variety of reactions.13 Among them,
Rueping demonstrated that the resulting α-amino radical could
undergo an intermolecular addition onto an imine.14
From these studies, we asked ourselves whether a
decarboxylative photoredox cyclization process might be
envisioned for the construction of 2-substituted piperazines.
In this Letter, we describe our work toward a photocatalytic
approach to the synthesis of such scaffolds from easily
available, environmentally benign amino-acid-based substrates.
In line with the SnAP and SLAP chemistry, we propose to
name this new annulation process the CarboxyLic Amine
Protocol (CLAP).
The viability of our approach was initially investigated on a
model reaction between the diamino acid 1 (easily available
from the natural amino acid glycine) and 4-fluorobenzaldehyde
2a. The reaction was performed under blue-light irradiation in
the presence of 1 mol % of the [Ir(ppy)2(dtbpy)]PF6 (Ir1)
photocatalyst (Table 1). In the first set of experiments, 2a was
B
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in the absence of photosensitizer (entry 18) or without
photoexcitation (entry 19), and this suggested that both are
necessary to promote the reaction.15
From this first successful set of experiments, a plausible
mechanism can already be proposed starting from the imine,
generated prior to irradiation by condensation between
diamine 1 and aldehyde 2a (Scheme 2). In the first step, the
92% yield. As exceptions, 4-cyanobenzaldehyde led to a lower,
albeit satisfactory, yield of 70%, whereas 4-nitrobenzaldehyde
failed to give the desired product. The heteroaromatics
thiofurfural, furfural, and nicotinaldehyde were good perform-
ers in this CLAP transformation, furnishing 3k, 3l, and 3m in
77, 87, and 80% yields, respectively. Among the aliphatic
aldehydes, cylohexanecarboxaldehyde and propanal yielded the
corresponding annulated adducts 3n and 3o in 99 and 87%
yield, respectively. Unfortunately, when the annulation process
was attempted with trifluoroacetaldehyde ethyl hemiacetal, the
2-trifluoromethyl piperazine was not obtained. Similarly, the
reactions with ketones failed during the prerequisite ketimine
formation. Despite several dehydration conditions tested, the
predominant product was the 4-benzylpiperazin-2-one, result-
ing from the intramolecular lactamization of substrate 1, with
no traces of the desired ketimine.
Scheme 2. Proposed Mechanism for Ir-based Catalyst
Following the development of the above carboxylic amine
protocol, we discovered that the transformation proceeds very
quickly under batch conditions, with the reaction being over in
∼30 min. This observation prompted us to transpose this
reaction from batch to continuous mode. Compared with
classical batch processes, an increased surface exposed to light
and more homogeneous irradiation are among the multiple
benefits of continuous-flow conditions for light-mediated
reactions.19 As a powerful tool in organic synthesis, flow
chemistry has now become common in a wide range of
chemical industries, including the pharmaceutical sector for
drug discovery, development, and manufacturing.20 In the
photocatalysis area, a good number of batch transformations
have been transposed to continuous-flow processes.21
The batch conditions for the carboxylic amine protocol were
not directly transposable to flow conditions due to the
presence of solids that could clog the flow device. A precipitate,
most probably potassium trifluoroacetate, forms during the
course of the reaction when KOH is used. This led us to
replace KOH by 1,8-diazabicyclo[5.4.0]undec-7-ene, which
does not form a precipitate during the reaction. In addition, we
decided to test the flow transformation in the presence of the
4CzIPN. This photocatalyst, despite its requirement for higher
loading than Ir1, is particularly cost-attractive and, being
purely organic, does not contain the expensive and potentially
toxic iridium heavy metal, residual traces of which would have
to be tightly controlled in the piperazine if the end use
included biological testing. (The permitted daily exposure for
Ir is 100 ppm/day for oral route administration and 10 ppm/
day for I.V.)
Similarly to the batch procedure, the imine was preformed
for 30 min before being mixed into a methanol/acetonitrile (4/
1) solution containing the photoinitiator (Table 2). After
degassing, the mobile phase was introduced into a Vaportec
photoreactor at an initial flow rate of 1.5 mL·min−1 within 6.7
min of residence time. This led to the piperazine 3a in 65%
isolated yield (entry 1). Gratifyingly, an improved yield of 80%
was obtained when the residence time was reduced to only 3
min (entry 3). Finally, a scale-up continuous experiment from
0.2 to 2.5 mmol led to the photoannulated adduct in 77%
isolated yield within ∼30 min (entry 5).
amino moiety is suspected to be oxidized by the photoexcited
iridium catalyst [Ir(ppy)2(dtbpy)]PF6.16 A consecutive de-
carboxylation would lead to the α-amino radical, which then
would undergo an intramolecular addition onto the imine.
From the resulting N-centered radical, two pathways can be
hypothesized. In accordance with the literature, following path
A, this latter radical might be reduced by the Ir(II) species to
give, after protonation by methanol or water, the piperazine.
Although this reduction might first seem to be unfavorable
red
(E1/2 = −1.70 V vs SCE for dialkylaminyl radicals and
E1/2red[Ir(III)/Ir(II)] = −1.51 V vs SCE), Bode has proposed a
stabilizing effect of the adjacent substituents, thus rendering
the reduction feasible.10 Because we found that the reaction
could be performed in the presence of 4CzIPN, which has an
even less favorable reduction potential (E1/2red(4CzIPN/
4CzIPN−) = −1.21 V vs SCE), we assume that another
mechanism could occur through path B. As such, we envision
that the N-centered radical could abstract a hydrogen atom
from acetonitrile (bond dissociation energy D298(H−CH2CN)
= 405.8
4.2 kJ mol−1)17 to afford the piperazine and the
cyanomethyl radical •CH2CN. The latter can be readily
reduced by the photocatalyst (E1/2red[•CH2CN/−CH2CN] =
−0.72 V),18 thereby closing the catalytic cycle.
With suitable conditions established, that is, 1 equiv of
amino acid, 1.4 equiv of aldehyde, 4.1 equiv of KOH, and 1
mol % of Ir1, the scope of the annulation process was
examined with a variety of aldehydes (Scheme 3). These
include diversely substituted benzaldehyde derivatives, hetero-
aromatics, as well as aliphatic aldehydes. For the benzalde-
hydes, this study revealed that a wide range of substituents,
including electron-donating or -withdrawing ones attached to
the benzaldehyde in the ortho, meta or para position, are well-
tolerated, furnishing the corresponding piperazines in up to
In summary, we have demonstrated that a straightforward
synthesis of 2-aryl, 2-heteroaryl, as well as 2-alkyl piperazines is
possible through a photoinitiated decarboxylative annulation
protocol between a diamine and a large variety of aldehydes.
Advantages include easy access to the building block 1 derived
from the natural amino acid glycine, the use of a purely organic
C
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Letter
a b
,
Scheme 3. Variation of Substrates
a
Each reaction was performed at room temperature under blue-light irradiation (34 W) on a 0.1 mmol scale of 1 in 0.05 M concentration in a
b
MeCN/MeOH (4/1) degassed solution. Values outside brackets are the isolated yields, and the values inside brackets are the NMR yields using
1,3,5-trimethoxybenzene as an internal standard. Few impurities remain after isolation.
c
current existing methods for the synthesis of 2-substituted
piperazines.
Table 2. Continuous Process Optimization
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01759.
Experimental procedures and accompanying analytical
data (1H and 13C NMR, IR, and MS) for all new
compounds (PDF)
entry
flow rate (mL·min−1
)
residence time (min)
yield (%)
1
2
3
4
5
1.5
2.5
3.33
5
6.7
4
3
2
3
65
76
80
75
AUTHOR INFORMATION
■
Corresponding Authors
a
Till Bousquet − Univ. Lille, CNRS, Centrale Lille, ENSCL,
Univ. Artois, UMR 8181, Unite de Catalyse et Chimie du
Solide, F-59000 Lille, France; orcid.org/0000-0003-3022-
3494; Email: till.bousquet@univ-lille.fr
3.33
77
́
a
Reaction performed with 2.5 mmol (1.09 g) of diamine.
photoredox catalyst, as well as the successful transposition of
this reaction from batch to flow conditions. These render the
newly developed CLAP protocol a powerful alternative to the
Antony Bigot − Pre Development Science Chemical Synthesis,
Sanofi, 94403 Vitry-Sur-Seine, France; orcid.org/0000-
0003-3320-3755; Email: antony.bigot@sanofi.com
D
https://dx.doi.org/10.1021/acs.orglett.0c01759
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Letter
O’Brien, P.; Campos, K. R. Diamine-Free Lithiation−Trapping of N-
Boc Heterocycles using s-BuLi in THF. Org. Lett. 2010, 12, 4176−
4179.
Authors
Robin Gueret − Univ. Lille, CNRS, Centrale Lille, ENSCL,
Univ. Artois, UMR 8181, Unite de Catalyse et Chimie du
Solide, F-59000 Lille, France
Lydie Pelinski − Univ. Lille, CNRS, Centrale Lille, ENSCL,
Univ. Artois, UMR 8181, Unite de Catalyse et Chimie du
Solide, F-59000 Lille, France
Mathieu Sauthier − Univ. Lille, CNRS, Centrale Lille, ENSCL,
Univ. Artois, UMR 8181, Unite de Catalyse et Chimie du
Solide, F-59000 Lille, France
Vincent Ferey − PDP Innovation, Sanofi, 34184 Montpellier,
France
́
(8) (a) Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.; Knowles, R.
R. Catalytic Olefin Hydroamination with Aminium Radical Cations: A
Photoredox Method for Direct C−N Bond Formation. J. Am. Chem.
Soc. 2014, 136, 12217−12220. (b) McNally, A.; Prier, C. K.;
MacMillan, D. W. C. Discovery of an α-Amino C−H Arylation
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A.; MacMillan, D. W. C. Photoredox α-Vinylation of α-Amino Acids
and N-Aryl Amines. J. Am. Chem. Soc. 2014, 136, 11602−11605.
(e) Bissonnette, N. B.; Ellis, J. M.; Hamann, L. G.; Romanov-
Michailidis, F. Expedient access to saturated nitrogen heterocycles by
photoredox cyclization of imino-tethered dihydropyridines. Chem. Sci.
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(9) (a) Vo, C.-V. T.; Mikutis, G.; Bode, J. W. SnAP Reagents for the
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Chem., Int. Ed. 2013, 52, 1705−1708. (b) Luescher, M. U.; Vo, C.-V.
T.; Bode, J. W. SnAP Reagents for the Synthesis of Piperazines and
Morpholines. Org. Lett. 2014, 16, 1236−1239. (c) Luescher, M. U.;
Bode, J. W. Catalytic Synthesis of N-Unprotected Piperazines,
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́
́
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01759
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Sanofi is gratefully acknowledged for financial support and for
a postdoctoral grant (R.G.). CNRS, Chevreul Institute (FR
■
̀
́
2638), Ministere de l’Enseignement Superieur et de la
Recherche, Region Nord − Pas de Calais, and FEDER are
acknowledged for supporting and partially funding this work.
́
́
We also thank Celine Delabre (UCCS) for the technical
support and Mr. Alexandre Farag (trainee in Sanofi) for initial
experiments, demonstrating the validity of the described
approach. Finally, we thank Dr. Andrew Van-Sickle (Vitry
Drug Substance, Sanofi) for the help with proofreading.
(11) Nakajima, K.; Nojima, S.; Sakata, K.; Nishibayashi, Y. Visible-
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Cleavage. ChemCatChem 2016, 8, 1028−1032.
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Amino Acids via Photoredox Catalysis: A One-Step Conversion of
Biomass to Drug Pharmacophore. J. Am. Chem. Soc. 2014, 136, 5257−
5260.
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